- Email: [email protected]
Treatment of rheumatoid arthritis with combination of methotrexate and Tripterygium wilfordii: A meta-analysis
Accepted Manuscript Treatment of rheumatoid arthritis with combination methotrexate and Tripterygium wilfordii: A meta-analysis
of
Xiaoyu Wang, Yunyun Zu, Lin Huang, Jie Yu, Huawei Zhao, Chengping Wen, Zhong Chen, Zhenghao Xu PII: DOI: Reference:
S0024-3205(17)30004-8 doi: 10.1016/j.lfs.2017.01.004 LFS 15122
To appear in:
Life Sciences
Received date: Revised date: Accepted date:
3 November 2016 29 December 2016 6 January 2017
Please cite this article as: Xiaoyu Wang, Yunyun Zu, Lin Huang, Jie Yu, Huawei Zhao, Chengping Wen, Zhong Chen, Zhenghao Xu , Treatment of rheumatoid arthritis with combination of methotrexate and Tripterygium wilfordii: A meta-analysis. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Lfs(2017), doi: 10.1016/j.lfs.2017.01.004
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Full length article Treatment of rheumatoid arthritis with combination of methotrexate and Tripterygium wilfordii: A meta-analysis Xiaoyu Wanga, 1, Yunyun Zu a, 1, Lin Huang a, Jie Yu a, Huawei Zhaob, Chengping Wen a,
College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou 310053,
RI
a
PT
Zhong Chen a, b, Zhenghao Xu a, *
b
SC
Zhejiang, China;
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of
NU
Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang
MA
University, Hangzhou, China
These authors contributed to this work equally.
*
Corresponding Author: Xu Zhenghao, PhD, Binwen Road 548, Hangzhou, Zhejiang, China,
D
1
AC
CE
PT E
tel & fax: +86-571-86613587, e-mail: [email protected] (Z. Xu)
1
ACCEPTED MANUSCRIPT Abstract Aims: Extracts of Tripterygium wilfordii Hook F (TwHF), a traditional Chinese herbal medicine, have been widely used for treating rheumatoid arthritis (RA) in combination with methotrexate (MTX) in China for several decades. However, the efficacy and safety of MTX
PT
plus TwHF treatment remain unclear.
RI
Main methods: A comprehensive search of databases in both Chinese and English was
SC
performed. Data from the selected studies were extracted and analyzed independently by two authors.
NU
Key findings: Six randomized controlled trials were included in the final analysis with a total
MA
of 643 patients. All trials added TwHF (in the form of Tripterygium glycosides) to the MTX-based therapy. For efficacy, the addition of TwHF increased 50% responder rates (RR)
D
(RR 1.337, 95% confidence interval [CI]: 1.188–1.505, P <0.001), and it reduced swollen
PT E
and tender joint counts, shortened the duration of morning stiffness, decreased the erythrocyte sedimentation rate, and decreased the level of C-reactive protein and rheumatoid factor. For
CE
safety, the addition of TwHF did not increase the rate of adverse events (RR 0.824, 95%
AC
CI:0.635–1.068, P = 0.143).
Significance: MTX plus TwHF therapy may be a more effective and similar safe strategy for treating RA compared to MTX monotherapy. Further large clinical trials to investigate the TwHF add-on therapy are warranted. Keywords: Rheumatoid arthritis; Tripterygium wilfordii; Methotrexate; Meta-analysis
2
ACCEPTED MANUSCRIPT Abbreviations ACR: American College of Rheumatology AEs: advent effects ALT: alanine transaminase
PT
CI: confidence interval
RI
CRP: C-reactive protein
SC
DMARDs: disease-modifying anti-rheumatoid drugs DMS: duration of morning stiffness
NU
ESR: erythrocyte sedimentation rate
MA
MTX: methotrexate RA: rheumatoid arthritis
TJC: tender joint counts
PT E
SJC: swollen joint counts
D
RRs: risk ratios
AC
CE
TwHF: Tripterygium wilfordii Hook F
3
ACCEPTED MANUSCRIPT 1. Introduction Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disorder that affects about 0.5–1.0% of the population, especially women and the elderly [1]. RA is characterized by systemic and synovial inflammation, and it leads to permanent joint damage
PT
and disability if uncontrolled. At present, synthetic disease-modifying anti-rheumatoid drugs
RI
(DMARDs), particularly methotrexate (MTX), are the first-line drugs to alleviate synovitis
SC
and systemic inflammation for treating RA [2]. Second-line immune-selective biologic agents (drugs) may be slightly more tolerable than synthetic DMARDs [3, 4]. However, the current
NU
pharmacologic therapies cannot produce an adequate response in many patients [5], and the
MA
new pharmacologic strategies for RA treatment are still warranted. Tripterygium wilfordii Hook F (TwHF) is a traditional Chinese medicine herb, and its
D
root has been used to treat RA in traditional Chinese medicine [6]. TwHF extracts have been
PT E
widely used and have even become a standard therapy in China for treating RA for several decades [7]. Increasing evidence has shown that TwHF extracts are efficacious for treating
CE
active RA, such as Tripterygium glycosides and triptolide [8-10]. Previous meta-analysis
AC
studies support that TwHF extracts are effective and safe for treating RA [11, 12]. In two small clinical trials, TwHF extracts also show good efficacy on RA on U.S. patients. [13, 14]. Recently, several randomized control trials further indicated that the addition of TwHF may be able to achieve better effectiveness than DMARDs monotherapy (such as MTX) in patients with RA [15, 16]. Actually, MTX plus TwHF has been empirically used for treating RA in China for decades [17, 18]. However, the evidence for the MTX plus TwHF therapy for RA remains inadequate, and it is necessary to have a quantitative meta-analysis of the 4
ACCEPTED MANUSCRIPT efficacy and safety of TwHF add-on therapy in patients with RA. Therefore, we performed a quantitative meta-analysis of the efficacy and safety of the combined use of TwHF with MTX for RA.
PT
2. Material and methods
RI
2.1 Literature search
SC
Two authors independently performed a systematic search of PubMed, Web of Science, and Clinical Trials.gov for clinical trials up to April 8, 2016. Comprehensive searching was
NU
conducted using the terms (“Tripterygium”, “leigongteng”, or “thunder god vine”) and
MA
(“rheumatoid arthritis”, “atrophic arthritis,” or “rheumatism”). In addition, we also searched Chinese databases, including Wan Fang Data, VIP, and CNKI, for Chinese-language studies
D
using the terms “lei gong teng” (for Tripterygium), “jia an die ling” (for MTX), and “guan jie
PT E
yan” (for arthritis) in Chinese. Chinese literature was further restricted to RA by reviewing the titles and abstracts. Our study was conducted according to the PRISMA (Preferred
AC
CE
Reporting Items for Systematic Reviews and Meta-Analyses) [19].
2.2 Selection criteria
The following criteria were adopted: (1) clinical randomized control trials (RCTs) aiming to study using MTX plus TwHF for treating RA; (2) a well-defined efficacy rate of 50% or American College of Rheumatology (ACR) 50 index (ACR50); (3) follow-up duration ≥3 months; (4) patients receiving a diagnosis of RA according to ACR guidelines; and (5) there are no other treatment factors between the combination and control group. 5
ACCEPTED MANUSCRIPT We excluded the following articles: (1) Non-RCTs; (2) incomplete or duplicative data; (3) follow-up duration <3 months; (4) people enrolled were not given a diagnosis according to ACR guidelines; and (5) there are additional treatment factors (such as drugs or Chinese
PT
medicine) in the combination group and/or the control group.
RI
2.3 Data extraction and quality assessment
SC
Similar to our previous study [20], two authors (X. W. and Y. Z.) independently browsed the title, abstract, and the full text of the literature meeting the criteria. Any discrepancies
NU
were resolved by consensus with the corresponding author (Z. X.). Each study’s clinical
MA
characteristics were summarized, and each study’s main outcomes were extracted or calculated. Adverse events (AEs) were also collected. Study quality was evaluated using a
D
modified Jadad scale [21] to assess reported randomization, blinding, withdrawals, dropouts,
PT E
inclusion/exclusion criteria, AEs, and the statistical analysis, with a maximum score of 8 points (supplementary table 1). Low-quality studies yielded scores of 0 to 3, and high-quality
CE
studies achieved scores of 4 to 8. In addition, to assess publication bias, Egger's test or Begg's
AC
funnel plot was performed, if possible.
2.4 Statistical analysis
Comprehensive meta-analysis was performed to calculate risk ratios (RRs) or mean difference, and their 95% confidence interval (CI) by comprehensive meta-analysis software V2.0. Statistical heterogeneity was assessed by Cochran’s Q statistic and the I2 statistic. The fixed-effect model was used to pool studies when statistical heterogeneity was absent and that 6
ACCEPTED MANUSCRIPT substantial heterogeneity was defined as I2 > 50% or chi-squared test P <0.1; otherwise, the random-effects model was employed.
3. Results
PT
3.1 RCT selection
RI
The study selection process is depicted in Fig. 1. Notably, two RCTs were excluded
SC
because they used MTX at 15 mg/kg in the control group but MTX at 7.5 mg/kg and MTX plus TwHF groups [18, 22], while another one was excluded because it was not an RCT
AC
CE
PT E
D
MA
NU
related to the MTX plus TwHF treatment [10].
7
ACCEPTED MANUSCRIPT Fig. 1. Flow diagram of the study selection process. Finally, six completed RCTs (n = 643) were included in the current meta-analysis [15, 16, 23-26]. All six RCTs used TwHF in the form of tripterygium glycosides, which is a tablet containing chloroform/methanol extract of TwHF [7, 17]. The dose of MTX was similar
PT
among the six study (about 10 mg/week), while the dose of TwHF differed among the six
RI
studies. One study used TwHF at 10 mg/d [23], two studies used TwHF at 30 mg/d [24, 25],
SC
and the other three studies used TwHF at 60 mg/d [15, 16, 26]. Lv et al. also tested the TwHF monotherapy in parallel [15]. The details of the included studies are summarized in Table 1.
NU
The details of the modified Jadad scale for each included study are shown in supplementary
MA
table 2.
Tan and Xiao 2010 [23]
52
[16]
AC
Yang et al. 2013 [24] Wang 2013 [25] Wang and Luan 2015 [26]
MTX (mg/w)
MTX+Tw HF (mg/d)
Duratio n (Weeks)
Modified JADAD score
52
10
+TG(10）
12
3
42
47
10-15
+TG(60）
12
3
40 50
40 76
10 15
+TG(30） +TG(30）
24 12
5 5
53
53
10
+TG(60）
12
4
CE
Zhang and Tan 2012
MTX+Tw HF (mg/d)
PT E
MTX (mg/ w)
Dose
D
Table 1 The details of included studies Study Number of patients
7.5-12. +TG(60） 12 5 5 MTX: methotrexate; TG: tripterygium glycosides; mg/w: mg/week; mg/d: mg/day. Lv et al. 2015 [15]
69
69
8
ACCEPTED MANUSCRIPT 3.2 Efficacy In addition to ACR50 or 50% RR (refer to effect rate), all six trials reported ACR20 or 30% RR (refer to improvement rate). As shown in figure 2, meta-analysis showed that the add-on of TwHF increased both improvement rate (RR 1.163, 95% CI: 1.087–1.245, P <
PT
0.001) and effect rate (RR 1.337, 95% CI: 1.188–1.505, P <0.001). The effect of TwHF
RI
seems to be dose-dependent, as shown by pooled responder in subgroups of different doses of
SC
TwHF (Table 2). Notably, the effect of 30 mg/d subgroup seems on 50% rate slightly stronger than that of 60 mg/d subgroup, which may be partly due to the following confounding factors:
NU
(1) the study of Yang et al. (the most efficacy study) [24] in 30 mg/d subgroup had a longer
MA
following duration (24 weeks) than other studies (12 weeks); and (2) the other included study of Wang [25] used a relatively higher dose of MTX (15 mg/week) than other studies (10-15
AC
CE
PT E
D
mg/week).
Fig. 2. Forest plot of the efficacy of MTX plus TwHF for treating active RA. MTX: methotrexate; TwHF: Tripterygium wilfordii Hook F. Weight%: weight coefficient. 0.000 of p-Value means P < 0.001. The included references: Tan and Xiao 2010 [23]; Zhang and Tan 9
ACCEPTED MANUSCRIPT 2012[16]; Yang et al. 2013[24]; Wang 2013[25]; Wang and Luan 2015[26]; Lv et al. 2015[15]. Table 2 The subgroup meta-analysis Subgroup Study
RR [95% Cl]
p-Value
(Dose of TwHF)
Tan and Xiao 2010 [23]
1.111 [0.985, 1.253]
Subtotal (Fixed model)
PT
0.086
1.111 [0.985, 1.253]
0.086
Yang et al. 2013 [24]
1.129 [0.921, 1.384]
0.244
Wang 2013 [25]
SC
30% response or ACR 20
1.096 [0.860, 1.398]
0.457
1.115 [0.954, 1.371]
0.170
1.078 [0.897, 1.294]
0.423
Wang and Luan 2015 [26]
1.186 [1.031, 1.365]
0.017
Lv et al. 2015 [15]
1.455 [1.203, 1.758]
<0.001
1.225 [1.045, 2.505]
0.012
1.143 [0.898, 1.454]
0.277
Subtotal (Fixed model)
1.143 [0.898, 1.454]
0.277
Yang et al. 2013 [24]
1.800 [1.143, 2.835]
0.011
Wang 2013 [25]
1.453 [1.050, 2.009]
0.024
Subtotal (Fixed model)
1.562 [1.200, 2.034]
0.001
Zhang and Tan 2012 [16]
1.277 [0.881, 1.850]
0.197
Wang and Luan 2015 [26]
1.222 [0.979, 1.525]
0.076
Lv et al. 2015 [15]
1.656 [1.246, 2.202]
0.001
Subtotal (Fixed model)
1.353 [1.155, 1.585]
<0.001
30 mg/kg
RI
10 mg/kg
60 mg/kg
MA
Zhang and Tan 2012 [16]
NU
Subtotal (Fixed model)
Subtotal (Random model)
D
50% response or ACR 50
Tan and Xiao 2010 [23]
60 mg/kg
CE AC
30 mg/kg
PT E
10 mg/kg
Further analyzing other related symptoms of RA, as shown in figure 3, we found that the addition of TwHF improved the swollen joint counts (SJC, difference in means 1.462, 95% CI: 0.316–2.608, P = 0.012), tender joint counts (TJC; difference in means 2.956, 95% CI: 10
ACCEPTED MANUSCRIPT 0.957–4.955, P = 0.004), duration of morning stiffness (DMS; difference in means 2.621, 95% CI: 3.319–39.922, P = 0.021), erythrocyte sedimentation rate (difference in means 7.080, 95% CI: 5.562–8.598, P <0.001), C-reactive protein (CRP; difference in means 2.778, 95% CI: 1.312–4.244, P < 0.001), and rheumatoid factor (difference in means 77.197, 95% CI:
CE
PT E
D
MA
NU
SC
RI
PT
-3.714–158.108, P = 0.061).
Fig. 3. Forest plot for the efficacy of MTX plus TwHF on the clinical symptoms and
AC
laboratorial indexes. SJC: swollen joint counts; TJC: tender joint counts; DMS: duration of morning stiffness; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; RF: rheumatoid factor. The included references: Tan and Xiao 2010 [23]; Zhang and Tan 2012 [16]; Yang et al. 2013 [24]; Wang and Luan 2015 [26]; Lv et al. 2015 [15].
11
ACCEPTED MANUSCRIPT 3.3 Safety Three trials reported AEs, and 122 out of 344 patients experienced at least one AE [15, 24, 25]. The addition of TwHF did not increase the total AE rate (RR 0.824, 95% CI:0.635–1.068, P = 0.143). One trial reported withdrawal events due to AEs (n = 3 in MTX
PT
group and n = 3 in MTX+TwHF group) [15], while the other two trials stated no withdrawal
RI
events. The addition of TwHF did not increase the withdrawal rate due to AEs (RR 0.950, 95%
SC
CI: 0.244–3.707, P = 0.942). Table 3 lists all AEs occurring in the three trials. All three trials reported the gastrointestinal reaction, alanine transaminase (ALT) elevation, and
NU
leukocytopenia. The addition of TwHF also did not increase the AE rate of the following:
MA
gastrointestinal reaction (RR 0.834, 95% CI: 0.562–1236, P = 0.365), ALT elevation (RR 0.632, 95% CI: 0.300–1.333, P = 0.228), and leukocytopenia (RR 0.809, 95% CI:
AC
CE
PT E
D
0.331–1.975, P = 0.642).
12
ACCEPTED MANUSCRIPT Table 3. Adverse events
40 11 4 None None None None None
MTX+ TwHF 76 8 1 None None None None None
None
None
None
None
None
None
3 None None
2 None None
2 None None
None
None
None None
MTX 50 11 1 None None None None None
MTX+ TwHF 69 34 24 10 1 2 6 1
69 43 30 7 1 1 10 3
344 122 65 17 2 3 16 4
None
3
2
5
None
8
11
19
3 None None
6 0 7
11 1 10
27 1 17
1
1
0
3
5
None
None
None
2
1
3
None
0
2
2
MA
NU
SC
MTX
Total event s
D
AC
MTX
Lv et al. 2015 [15]
None
None 2
None 2
None 2
None 4
0 5
2 4
2 19
None
None
None
None
14
14
28
None 1 1 None 3
None 1 1 None 2
None None None None None
None None None None None
1 5 5 2 6
1 2 3 1 8
2 9 10 3 19
None
None
None
None
5
3
8
None None None None None None None None
None None None None None None None None
None None None None None None None 2
None None None None None None None 2
1 1 6 1 0 2 2 13
5 3 7 3 1 0 3 16
6 4 13 4 1 2 5 33
CE
Number of patients Patients with AEsa Gastrointestinala Nausea Vomiting Regurgitation Loss of appetite Diarrhoea Abdominal distention Abdominal discomfort ALT elevationa GGT elevation Infection, Upper respiratory tract infection Pneumonia Urinary tract infection Vaginitis Leucocytopeniaa Skin and mucous event Dry skin Rash Baldness Skin pigmentation Ulcer Irregular menstruation Fatigue Weight loss Anemia Palpitations Haematuria Peripheral oedema Headache Other adverse events
MTX+ TwHF 40 15 5 None None None None None
None
PT E
Adverse events (n)
Wang 2013 [25]
PT
[24]
RI
Yang et al. 2013
13
ACCEPTED MANUSCRIPT a
: meta-analysis (fixed model) were did for these adverse events: Patients with AEs: (RR
0.824, 95% CI:0.635–1.068, P = 0.143); Gastrointestinal reaction: (RR 0.834, 95% CI: 0.562–1236, P = 0.365); ALT elevation: (RR 0.632, 95% CI: 0.300–1.333, P = 0.228); Leucocytopenia: (RR 0.809, 95% CI: 0.331–1.975, P = 0.642). 4. Discussion
PT
In recent decades, TwHF plus MTX has become a common strategy for treating RA in
RI
China. Here, we proved the systematic evidence that the MTX plus TwHF may be more
SC
effective than MTX monotherapy for treating active RA. For efficacy, the addition of TwHF increased both the improvement rate (30% response or ACR20) and effective rate (50%
NU
response or ACR50) compared to MTX monotherapy. The addition of TwHF also reduced the
MA
SJC and TJC, shortened the DMS, decreased the level of CRP and rheumatoid factor, and reduced the ERS. TwHF’s effect seems to be dose-dependent, as shown by pooled responder
D
in subgroups of different doses of TwHF (Table 2). Regarding safety, MTX plus TwHF did
PT E
not increase the risk of AEs compared to MTX monotherapy. Thus, taken together, these clinical data indicate that MTX plus TwHF therapy may be a promising therapeutic strategy
CE
for RA.
AC
Two recent meta-analysis studies have also found TwHF extracts, including the tripterygium glycosides, are as effective as, or even more effective than, synthetic DMARDs for treating RA [11, 12]. However, these studies do not focus on combination use of TwHF with other RA drugs, and they the excluded most trials investigating combination therapies. Our study provides additional evidence for use of MTX plus TwHF for treating RA. In addition, two studies, which were excluded because they used MTX at 15 mg/kg in the control group but MTX at 7.5 mg/kg in the MTX plus TwHF groups, found that MTX (7.5 14
ACCEPTED MANUSCRIPT mg/weak) combined with TwHF (30 mg/kg) achieved better or equivalent effect than with MTX (15 mg/d) alone [18, 22]. In addition, Lv et al. recently found that MTX plus TwHF therapy was superior to both MTX and TwHF monotherapies for treating RA [15]. Thus, further large clinical studies are still needed to investigate the long-term efficacy, safety, and
PT
optimized dosages of the combination use of MTX and TwHF for treating RA.
RI
Several limitations in our meta-analysis should be noted: (1) methodologic quality in the
SC
research is poor in some trials, such as unclear random method and that the double blind method is not applied; (2) the included trials were conducted in Chinese population, which
NU
implied a high risk of selection bias; and (3) other interference factors exist, such as
MA
difference in drug dosage.
In addition, to explore some theoretical evidences of MTX plus TwHF therapy for
D
treating RA, we did some preliminary systems biological analyses (detailed information
PT E
please see supplementary information) as in our previous studies [27, 28]. We collected the trusted high confident targets (with comprehensive scores >0.7) of known compounds of
CE
TwHF ingredients from the STITCH database [29], and we compared them to the protein
AC
targets of approved RA drugs (including MTX) from DrugBank (http://www.drugbank.ca) [30] and Pharmainformatics Database (http://bidd.nus.edu.sg/) [31]. As shown in supplementary Fig. 1, we found that TwHF may not inhibited same targets as MTX, but TwHF seems to modulate many targets of other RA drugs, including tumor necrosis factor (TNF , target of etanercept, adalimumab, and infliximab), Prostaglandin G/H synthase 2 (PTGS2, target of etoricoxib), hypoxanthine-guanine phosphoribosyltransferase 1 (HPRT1, target of azathioprine), CD80 (target of belatacept and abatacept), CD86 (target of belatacept 15
ACCEPTED MANUSCRIPT and abatacept), and inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB, target of sulfasalazine). Moreover, by Go-term analysis of all targets of TwHF and MTX , we revealed that TwHF plus MTX may have a combined action on lymphocyte proliferation and its related pathways (as shown in supplementary Fig. 2 and 3). Thus, these systems biological
PT
data additionally support the use of TwHF plus MTX for treating RA, although we may only
RI
collect limited number of targets of TwHF. For example, it has been found triptolide, perhaps
SC
the most effective component of TwHF for treating RA, can block gene transcription by inhibiting transcription factor II Human (TFIIH, a component of transcription machinery)
NU
[32] and may modulate much more genes and proteins than that we collected here [33]. So
MA
the underlying targets and mechanisms concerning anti-rheumatic effect of TwHF are far
D
more complex than our analysis and remain to be further studied.
PT E
Conclusion
The current study preliminarily indicated that MTX plus TwHF may be a more effective
CE
and similarly safe strategy for treating active RA compared with MTX alone. One included
AC
study also suggests MTX plus TwHF may be a more effective strategy for treating active RA compared with TwHF alone [15]. Further large clinical studies are still needed to investigate the long-term efficacy and safety of the addition of TwHF for treating RA.
Conflict of interest None.
16
ACCEPTED MANUSCRIPT Acknowledgments This work was funded by Zhejiang Provincial Natural Science Foundation of China (LY16H280005) and the National Natural Science Foundation of China (81673623), partly supported by “Xin Miao” Student Research Program of Zhejiang Province (2015R410052)
AC
CE
PT E
D
MA
NU
SC
RI
PT
and the Research Program of Zhejiang Chinese Medical University (2015ZG03).
17
ACCEPTED MANUSCRIPT References
AC
CE
PT E
D
MA
NU
SC
RI
PT
[1] D.L. Scott, F. Wolfe, T.W. Huizinga. Rheumatoid arthritis, Lancet. 376 (9746) (2010) 1094-1108. [2] D. Aletaha, T. Neogi, A.J. Silman, J. Funovits, D.T. Felson, C.O. Bingham, 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative, Arthritis Rheum. 62 (9) (2010) 2569-2581. [3] L. Semerano, E. Minichiello, N. Bessis, M.C. Boissier. Novel Immunotherapeutic Avenues for Rheumatoid Arthritis, Trends Mol Med. 22 (3) (2016) 214-229. [4] M.E. Suarez-Almazor, E. Belseck, B. Shea, G. Wells, P. Tugwell. Methotrexate for rheumatoid arthritis, Cochrane Database Syst Rev. (2) (2000) CD000957. [5] E. Zampeli, P.G. Vlachoyiannopoulos, A.G. Tzioufas. Treatment of rheumatoid arthritis: Unraveling the conundrum, J Autoimmun. 65 (2015) 1-18. [6] J.L. Guo, S.X. Yuan, X.C. Wang, S.X. Xu, D.D. Li. Tripterygium wilfordii Hook f in rheumatoid arthritis and ankylosing spondylitis. Preliminary report, Chin Med J (Engl). 94 (7) (1981) 405-412. [7] X.L. Tao, Y. Dong, N.Z. Zhang. A double-blind study of T2 (tablets of polyglycosides of Tripterygium wilfodii hook) in the treatment of rheumatoid arthritis [in Chinese], Zhonghua Nei Ke Za Zhi. 26 (7) (1987) 399-402, 444-395. PMID: 3322706 [8] J. Cibere, Z. Deng, Y. Lin, R. Ou, Y. He, Z. Wang, et al. A randomized double blind, placebo controlled trial of topical Tripterygium wilfordii in rheumatoid arthritis: reanalysis using logistic regression analysis, J Rheumatol. 30 (3) (2003) 465-467. [9] W. Tang, J.P. Zuo. Immunosuppressant discovery from Tripterygium wilfordii Hook f: the novel triptolide analog (5R)-5-hydroxytriptolide (LLDT-8), Acta Pharmacologica Sinica. 33 (9) (2012) 1112-1118. [10] M. Jiang, Q. Zha, C. Zhang, C. Lu, X. Yan, W. Zhu, et al. Predicting and verifying outcome of Tripterygium wilfordii Hook F. based therapy in rheumatoid arthritis: from open to double-blinded randomized trial, Sci Rep. 5 (2016) 9700. [11] H.L. Wang, Q. Jiang, X.H. Feng, H.D. Zhang, L. Ge, C.G. Luo, et al. Tripterygium wilfordii Hook F versus conventional synthetic disease-modifying anti-rheumatic drugs as monotherapy for rheumatoid arthritis: a systematic review and network meta-analysis, BMC Complement Altern Med. 16 (2016) 215. [12] Y. Liu, S. Tu, W. Gao, Y. Wang, P. Liu, Y. Hu, et al. Extracts of Tripterygium wilfordii Hook F in the Treatment of Rheumatoid Arthritis: A Systemic Review and Meta-Analysis of Randomised Controlled Trials, Evid Based Complement Alternat Med. 2013 (2013) 410793. [13] R. Goldbach-Mansky, M. Wilson, R. Fleischmann, N. Olsen, J. Silverfield, P. Kempf, et al. Comparison of Tripterygium wilfordii Hook F versus sulfasalazine in the treatment of rheumatoid arthritis: a randomized trial, Ann Intern Med. 151 (4) (2009) 229-240, w249-251. [14] X. Tao, J. Younger, F.Z. Fan, B. Wang, P.E. Lipsky. Benefit of an extract of Tripterygium Wilfordii Hook F in patients with rheumatoid arthritis: a double-blind, placebo-controlled study, Arthritis Rheum. 46 (7) (2002) 1735-1743. [15] Q.W. Lv, W. Zhang, Q. Shi, W.J. Zheng, X. Li, H. Chen, et al. Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid 18
ACCEPTED MANUSCRIPT
AC
CE
PT E
D
MA
NU
SC
RI
PT
arthritis (TRIFRA): a randomised, controlled clinical trial, Annals Of the Rheumatic Diseases. 74 (6) (2015) 1078-1086. [16] X. Zhang, J. Tan. Clinical investigation of tripterygium glycosides plus methotrexate for treatment of rheumatoid arthritis [in Chinese], Chinese Journal of Medical Guide. (z2) (2012) 602-603. Doi: 10.3969/j.issn.1009-0959.2012.z2.129 [17] W. Zhang, Q. Shi, L.D. Zhao, Y. Li, F.L. Tang, F.C. Zhang, et al. The safety and effectiveness of a chloroform/methanol extract of Tripterygium wilfordii Hook F (T2) plus methotrexate in treating rheumatoid arthritis, J Clin Rheumatol. 16 (8) (2010) 375-378. [18] Y. Wu, Z. Lao, Z. Zhang. Clinical observation on small doses Tripterygium wilfordii polyglycoside combined with methotrexate in treating rheumatoid arthritis [in Chinese], Chinese journal of integrated traditional and Western medicine. 21 (12) (2001) 895-896. Doi: 10.3321/j.issn:1003-5370.2001.12.005 [19] D. Moher, A. Liberati, J. Tetzlaff, D.G. Altman, P. Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, PLoS Med. 6 (7) (2009) e1000097. [20]Z. Xu, H. Zhao, Z. Chen. The efficacy and safety of rufinamide in drug-resistant epilepsy: A meta-analysis of double-blind, randomized, placebo controlled trials, Epilepsy Res. 120 (2016) 104-110. [21] M. Oremus, C. Wolfson, A. Perrault, L. Demers, F. Momoli, Y. Moride. Interrater reliability of the modified Jadad quality scale for systematic reviews of Alzheimer's disease drug trials, Dement Geriatr Cogn Disord. 12 (3) (2001) 232-236. [22] J. Shen, Z. Zhang. Clinical Observation on the Treatment of Rheumatoid Arthritis with Tripterygium Glycosides and Low Dosage Methopterin [in Chinese], Zhejiang journal of integrated traditional chinese and western medicine. 12 (6) (2002) 334-336. Doi: 10.3969/j.issn.1005-4561.2002.06.002 [23] Q. Tan, Q. Xiao. Clinical Evaluation of Tripterygium Wilfordii Polyglycosidium Combined with Methotrexate in Treating Rheumatoid Arthritis and Its Effect on TNF-α and IL-6 [in Chinese], Chinese Journal of Information on Traditional Chinese Medicine. 17 (9) (2010) 7-9. Doi: 10.3969/j.issn.1005-5304.2010.09.004 [24] M. Yang, R. Zhou, B. Li, J. Xu, Y. Shi, H. Mo. Clinical Observation on treatment of rheumatoid arthritis with Tripterygium Wilfordii polyglycoside combined with methotrexate [in Chinese], Chinese Journal of Experimental Traditional Medical Formulae. 19 (17) (2013) 300-304. Doi: 10.11653/syfj2013170300 [25] Y. Wang. Invistagtion of the effcaciou of the cobination of Tripterygium wilfordii with methotrexate treatmet on the rheumatoid arthritis [in Chinese]. Chinese Journal of Primary Medicine and Pharmacy. 20 (11) (2013) 1678-1680. Doi: 10.3760/cma.j.issn.1008-6706.2013.11.038 [26] X. Wang, Z. Luan. Clinical observation on the treatment of rheumatoid arthritis with tripterygium glycosides and methotrexate [in Chinese]. , International Medicine and Health Guidance News. 21 (17) (2015) 2598-2600. Doi: 10.3969/j.issn.1005-4561.2002.06.002 [27] L. Huang, Q. Lv, D. Xie, T. Shi, C. Wen. Deciphering the Potential Pharmaceutical Mechanism of Chinese Traditional Medicine (Gui-Zhi-Shao-Yao-Zhi-Mu) on Rheumatoid Arthritis, Sci Rep. 6 (2016) 22602. [28] L. Huang, Q. Lv, F. Liu, T. Shi, C. Wen. A Systems Biology-Based Investigation into the 19
ACCEPTED MANUSCRIPT
AC
CE
PT E
D
MA
NU
SC
RI
PT
Pharmacological Mechanisms of Sheng-ma-bie-jia-tang Acting on Systemic Lupus Erythematosus by Multi-Level Data Integration, Sci Rep. 5 (2015) 16401. [29] M. Kuhn, C. von Mering, M. Campillos, L.J. Jensen, P. Bork. STITCH: interaction networks of chemicals and proteins, Nucleic Acids Res. 36 (Database issue) (2008) D684-688. [30] V. Law, C. Knox, Y. Djoumbou, T. Jewison, A.C. Guo, Y. Liu, et al. DrugBank 4.0: shedding new light on drug metabolism, Nucleic Acids Res. 42 (Database issue) (2014) D1091-1097. [31] H. Yang, C. Qin, Y.H. Li, L. Tao, J. Zhou, C.Y. Yu, et al. Therapeutic target database update 2016: enriched resource for bench to clinical drug target and targeted pathway information, Nucleic Acids Res. 44 (D1) (2016) D1069-1074. [32] D.V. Titov, B. Gilman, Q.L. He, S. Bhat, W.K. Low, Y. Dang, et al. XPB, a subunit of TFIIH, is a target of the natural product triptolide, Nat Chem Biol. 7 (3) (2011) 182-188. [33] R. Matta, X.X. Wang, H. Ge, W. Ray, L.D. Nelin, Y.S. Liu. Triptolide induces anti-inflammatory cellular responses, American Journal Of Translational Research. 1 (3) (2009) 267-282.
20
of
Xiaoyu Wang, Yunyun Zu, Lin Huang, Jie Yu, Huawei Zhao, Chengping Wen, Zhong Chen, Zhenghao Xu PII: DOI: Reference:
S0024-3205(17)30004-8 doi: 10.1016/j.lfs.2017.01.004 LFS 15122
To appear in:
Life Sciences
Received date: Revised date: Accepted date:
3 November 2016 29 December 2016 6 January 2017
Please cite this article as: Xiaoyu Wang, Yunyun Zu, Lin Huang, Jie Yu, Huawei Zhao, Chengping Wen, Zhong Chen, Zhenghao Xu , Treatment of rheumatoid arthritis with combination of methotrexate and Tripterygium wilfordii: A meta-analysis. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Lfs(2017), doi: 10.1016/j.lfs.2017.01.004
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Full length article Treatment of rheumatoid arthritis with combination of methotrexate and Tripterygium wilfordii: A meta-analysis Xiaoyu Wanga, 1, Yunyun Zu a, 1, Lin Huang a, Jie Yu a, Huawei Zhaob, Chengping Wen a,
College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou 310053,
RI
a
PT
Zhong Chen a, b, Zhenghao Xu a, *
b
SC
Zhejiang, China;
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of
NU
Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang
MA
University, Hangzhou, China
These authors contributed to this work equally.
*
Corresponding Author: Xu Zhenghao, PhD, Binwen Road 548, Hangzhou, Zhejiang, China,
D
1
AC
CE
PT E
tel & fax: +86-571-86613587, e-mail: [email protected] (Z. Xu)
1
ACCEPTED MANUSCRIPT Abstract Aims: Extracts of Tripterygium wilfordii Hook F (TwHF), a traditional Chinese herbal medicine, have been widely used for treating rheumatoid arthritis (RA) in combination with methotrexate (MTX) in China for several decades. However, the efficacy and safety of MTX
PT
plus TwHF treatment remain unclear.
RI
Main methods: A comprehensive search of databases in both Chinese and English was
SC
performed. Data from the selected studies were extracted and analyzed independently by two authors.
NU
Key findings: Six randomized controlled trials were included in the final analysis with a total
MA
of 643 patients. All trials added TwHF (in the form of Tripterygium glycosides) to the MTX-based therapy. For efficacy, the addition of TwHF increased 50% responder rates (RR)
D
(RR 1.337, 95% confidence interval [CI]: 1.188–1.505, P <0.001), and it reduced swollen
PT E
and tender joint counts, shortened the duration of morning stiffness, decreased the erythrocyte sedimentation rate, and decreased the level of C-reactive protein and rheumatoid factor. For
CE
safety, the addition of TwHF did not increase the rate of adverse events (RR 0.824, 95%
AC
CI:0.635–1.068, P = 0.143).
Significance: MTX plus TwHF therapy may be a more effective and similar safe strategy for treating RA compared to MTX monotherapy. Further large clinical trials to investigate the TwHF add-on therapy are warranted. Keywords: Rheumatoid arthritis; Tripterygium wilfordii; Methotrexate; Meta-analysis
2
ACCEPTED MANUSCRIPT Abbreviations ACR: American College of Rheumatology AEs: advent effects ALT: alanine transaminase
PT
CI: confidence interval
RI
CRP: C-reactive protein
SC
DMARDs: disease-modifying anti-rheumatoid drugs DMS: duration of morning stiffness
NU
ESR: erythrocyte sedimentation rate
MA
MTX: methotrexate RA: rheumatoid arthritis
TJC: tender joint counts
PT E
SJC: swollen joint counts
D
RRs: risk ratios
AC
CE
TwHF: Tripterygium wilfordii Hook F
3
ACCEPTED MANUSCRIPT 1. Introduction Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disorder that affects about 0.5–1.0% of the population, especially women and the elderly [1]. RA is characterized by systemic and synovial inflammation, and it leads to permanent joint damage
PT
and disability if uncontrolled. At present, synthetic disease-modifying anti-rheumatoid drugs
RI
(DMARDs), particularly methotrexate (MTX), are the first-line drugs to alleviate synovitis
SC
and systemic inflammation for treating RA [2]. Second-line immune-selective biologic agents (drugs) may be slightly more tolerable than synthetic DMARDs [3, 4]. However, the current
NU
pharmacologic therapies cannot produce an adequate response in many patients [5], and the
MA
new pharmacologic strategies for RA treatment are still warranted. Tripterygium wilfordii Hook F (TwHF) is a traditional Chinese medicine herb, and its
D
root has been used to treat RA in traditional Chinese medicine [6]. TwHF extracts have been
PT E
widely used and have even become a standard therapy in China for treating RA for several decades [7]. Increasing evidence has shown that TwHF extracts are efficacious for treating
CE
active RA, such as Tripterygium glycosides and triptolide [8-10]. Previous meta-analysis
AC
studies support that TwHF extracts are effective and safe for treating RA [11, 12]. In two small clinical trials, TwHF extracts also show good efficacy on RA on U.S. patients. [13, 14]. Recently, several randomized control trials further indicated that the addition of TwHF may be able to achieve better effectiveness than DMARDs monotherapy (such as MTX) in patients with RA [15, 16]. Actually, MTX plus TwHF has been empirically used for treating RA in China for decades [17, 18]. However, the evidence for the MTX plus TwHF therapy for RA remains inadequate, and it is necessary to have a quantitative meta-analysis of the 4
ACCEPTED MANUSCRIPT efficacy and safety of TwHF add-on therapy in patients with RA. Therefore, we performed a quantitative meta-analysis of the efficacy and safety of the combined use of TwHF with MTX for RA.
PT
2. Material and methods
RI
2.1 Literature search
SC
Two authors independently performed a systematic search of PubMed, Web of Science, and Clinical Trials.gov for clinical trials up to April 8, 2016. Comprehensive searching was
NU
conducted using the terms (“Tripterygium”, “leigongteng”, or “thunder god vine”) and
MA
(“rheumatoid arthritis”, “atrophic arthritis,” or “rheumatism”). In addition, we also searched Chinese databases, including Wan Fang Data, VIP, and CNKI, for Chinese-language studies
D
using the terms “lei gong teng” (for Tripterygium), “jia an die ling” (for MTX), and “guan jie
PT E
yan” (for arthritis) in Chinese. Chinese literature was further restricted to RA by reviewing the titles and abstracts. Our study was conducted according to the PRISMA (Preferred
AC
CE
Reporting Items for Systematic Reviews and Meta-Analyses) [19].
2.2 Selection criteria
The following criteria were adopted: (1) clinical randomized control trials (RCTs) aiming to study using MTX plus TwHF for treating RA; (2) a well-defined efficacy rate of 50% or American College of Rheumatology (ACR) 50 index (ACR50); (3) follow-up duration ≥3 months; (4) patients receiving a diagnosis of RA according to ACR guidelines; and (5) there are no other treatment factors between the combination and control group. 5
ACCEPTED MANUSCRIPT We excluded the following articles: (1) Non-RCTs; (2) incomplete or duplicative data; (3) follow-up duration <3 months; (4) people enrolled were not given a diagnosis according to ACR guidelines; and (5) there are additional treatment factors (such as drugs or Chinese
PT
medicine) in the combination group and/or the control group.
RI
2.3 Data extraction and quality assessment
SC
Similar to our previous study [20], two authors (X. W. and Y. Z.) independently browsed the title, abstract, and the full text of the literature meeting the criteria. Any discrepancies
NU
were resolved by consensus with the corresponding author (Z. X.). Each study’s clinical
MA
characteristics were summarized, and each study’s main outcomes were extracted or calculated. Adverse events (AEs) were also collected. Study quality was evaluated using a
D
modified Jadad scale [21] to assess reported randomization, blinding, withdrawals, dropouts,
PT E
inclusion/exclusion criteria, AEs, and the statistical analysis, with a maximum score of 8 points (supplementary table 1). Low-quality studies yielded scores of 0 to 3, and high-quality
CE
studies achieved scores of 4 to 8. In addition, to assess publication bias, Egger's test or Begg's
AC
funnel plot was performed, if possible.
2.4 Statistical analysis
Comprehensive meta-analysis was performed to calculate risk ratios (RRs) or mean difference, and their 95% confidence interval (CI) by comprehensive meta-analysis software V2.0. Statistical heterogeneity was assessed by Cochran’s Q statistic and the I2 statistic. The fixed-effect model was used to pool studies when statistical heterogeneity was absent and that 6
ACCEPTED MANUSCRIPT substantial heterogeneity was defined as I2 > 50% or chi-squared test P <0.1; otherwise, the random-effects model was employed.
3. Results
PT
3.1 RCT selection
RI
The study selection process is depicted in Fig. 1. Notably, two RCTs were excluded
SC
because they used MTX at 15 mg/kg in the control group but MTX at 7.5 mg/kg and MTX plus TwHF groups [18, 22], while another one was excluded because it was not an RCT
AC
CE
PT E
D
MA
NU
related to the MTX plus TwHF treatment [10].
7
ACCEPTED MANUSCRIPT Fig. 1. Flow diagram of the study selection process. Finally, six completed RCTs (n = 643) were included in the current meta-analysis [15, 16, 23-26]. All six RCTs used TwHF in the form of tripterygium glycosides, which is a tablet containing chloroform/methanol extract of TwHF [7, 17]. The dose of MTX was similar
PT
among the six study (about 10 mg/week), while the dose of TwHF differed among the six
RI
studies. One study used TwHF at 10 mg/d [23], two studies used TwHF at 30 mg/d [24, 25],
SC
and the other three studies used TwHF at 60 mg/d [15, 16, 26]. Lv et al. also tested the TwHF monotherapy in parallel [15]. The details of the included studies are summarized in Table 1.
NU
The details of the modified Jadad scale for each included study are shown in supplementary
MA
table 2.
Tan and Xiao 2010 [23]
52
[16]
AC
Yang et al. 2013 [24] Wang 2013 [25] Wang and Luan 2015 [26]
MTX (mg/w)
MTX+Tw HF (mg/d)
Duratio n (Weeks)
Modified JADAD score
52
10
+TG(10）
12
3
42
47
10-15
+TG(60）
12
3
40 50
40 76
10 15
+TG(30） +TG(30）
24 12
5 5
53
53
10
+TG(60）
12
4
CE
Zhang and Tan 2012
MTX+Tw HF (mg/d)
PT E
MTX (mg/ w)
Dose
D
Table 1 The details of included studies Study Number of patients
7.5-12. +TG(60） 12 5 5 MTX: methotrexate; TG: tripterygium glycosides; mg/w: mg/week; mg/d: mg/day. Lv et al. 2015 [15]
69
69
8
ACCEPTED MANUSCRIPT 3.2 Efficacy In addition to ACR50 or 50% RR (refer to effect rate), all six trials reported ACR20 or 30% RR (refer to improvement rate). As shown in figure 2, meta-analysis showed that the add-on of TwHF increased both improvement rate (RR 1.163, 95% CI: 1.087–1.245, P <
PT
0.001) and effect rate (RR 1.337, 95% CI: 1.188–1.505, P <0.001). The effect of TwHF
RI
seems to be dose-dependent, as shown by pooled responder in subgroups of different doses of
SC
TwHF (Table 2). Notably, the effect of 30 mg/d subgroup seems on 50% rate slightly stronger than that of 60 mg/d subgroup, which may be partly due to the following confounding factors:
NU
(1) the study of Yang et al. (the most efficacy study) [24] in 30 mg/d subgroup had a longer
MA
following duration (24 weeks) than other studies (12 weeks); and (2) the other included study of Wang [25] used a relatively higher dose of MTX (15 mg/week) than other studies (10-15
AC
CE
PT E
D
mg/week).
Fig. 2. Forest plot of the efficacy of MTX plus TwHF for treating active RA. MTX: methotrexate; TwHF: Tripterygium wilfordii Hook F. Weight%: weight coefficient. 0.000 of p-Value means P < 0.001. The included references: Tan and Xiao 2010 [23]; Zhang and Tan 9
ACCEPTED MANUSCRIPT 2012[16]; Yang et al. 2013[24]; Wang 2013[25]; Wang and Luan 2015[26]; Lv et al. 2015[15]. Table 2 The subgroup meta-analysis Subgroup Study
RR [95% Cl]
p-Value
(Dose of TwHF)
Tan and Xiao 2010 [23]
1.111 [0.985, 1.253]
Subtotal (Fixed model)
PT
0.086
1.111 [0.985, 1.253]
0.086
Yang et al. 2013 [24]
1.129 [0.921, 1.384]
0.244
Wang 2013 [25]
SC
30% response or ACR 20
1.096 [0.860, 1.398]
0.457
1.115 [0.954, 1.371]
0.170
1.078 [0.897, 1.294]
0.423
Wang and Luan 2015 [26]
1.186 [1.031, 1.365]
0.017
Lv et al. 2015 [15]
1.455 [1.203, 1.758]
<0.001
1.225 [1.045, 2.505]
0.012
1.143 [0.898, 1.454]
0.277
Subtotal (Fixed model)
1.143 [0.898, 1.454]
0.277
Yang et al. 2013 [24]
1.800 [1.143, 2.835]
0.011
Wang 2013 [25]
1.453 [1.050, 2.009]
0.024
Subtotal (Fixed model)
1.562 [1.200, 2.034]
0.001
Zhang and Tan 2012 [16]
1.277 [0.881, 1.850]
0.197
Wang and Luan 2015 [26]
1.222 [0.979, 1.525]
0.076
Lv et al. 2015 [15]
1.656 [1.246, 2.202]
0.001
Subtotal (Fixed model)
1.353 [1.155, 1.585]
<0.001
30 mg/kg
RI
10 mg/kg
60 mg/kg
MA
Zhang and Tan 2012 [16]
NU
Subtotal (Fixed model)
Subtotal (Random model)
D
50% response or ACR 50
Tan and Xiao 2010 [23]
60 mg/kg
CE AC
30 mg/kg
PT E
10 mg/kg
Further analyzing other related symptoms of RA, as shown in figure 3, we found that the addition of TwHF improved the swollen joint counts (SJC, difference in means 1.462, 95% CI: 0.316–2.608, P = 0.012), tender joint counts (TJC; difference in means 2.956, 95% CI: 10
ACCEPTED MANUSCRIPT 0.957–4.955, P = 0.004), duration of morning stiffness (DMS; difference in means 2.621, 95% CI: 3.319–39.922, P = 0.021), erythrocyte sedimentation rate (difference in means 7.080, 95% CI: 5.562–8.598, P <0.001), C-reactive protein (CRP; difference in means 2.778, 95% CI: 1.312–4.244, P < 0.001), and rheumatoid factor (difference in means 77.197, 95% CI:
CE
PT E
D
MA
NU
SC
RI
PT
-3.714–158.108, P = 0.061).
Fig. 3. Forest plot for the efficacy of MTX plus TwHF on the clinical symptoms and
AC
laboratorial indexes. SJC: swollen joint counts; TJC: tender joint counts; DMS: duration of morning stiffness; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; RF: rheumatoid factor. The included references: Tan and Xiao 2010 [23]; Zhang and Tan 2012 [16]; Yang et al. 2013 [24]; Wang and Luan 2015 [26]; Lv et al. 2015 [15].
11
ACCEPTED MANUSCRIPT 3.3 Safety Three trials reported AEs, and 122 out of 344 patients experienced at least one AE [15, 24, 25]. The addition of TwHF did not increase the total AE rate (RR 0.824, 95% CI:0.635–1.068, P = 0.143). One trial reported withdrawal events due to AEs (n = 3 in MTX
PT
group and n = 3 in MTX+TwHF group) [15], while the other two trials stated no withdrawal
RI
events. The addition of TwHF did not increase the withdrawal rate due to AEs (RR 0.950, 95%
SC
CI: 0.244–3.707, P = 0.942). Table 3 lists all AEs occurring in the three trials. All three trials reported the gastrointestinal reaction, alanine transaminase (ALT) elevation, and
NU
leukocytopenia. The addition of TwHF also did not increase the AE rate of the following:
MA
gastrointestinal reaction (RR 0.834, 95% CI: 0.562–1236, P = 0.365), ALT elevation (RR 0.632, 95% CI: 0.300–1.333, P = 0.228), and leukocytopenia (RR 0.809, 95% CI:
AC
CE
PT E
D
0.331–1.975, P = 0.642).
12
ACCEPTED MANUSCRIPT Table 3. Adverse events
40 11 4 None None None None None
MTX+ TwHF 76 8 1 None None None None None
None
None
None
None
None
None
3 None None
2 None None
2 None None
None
None
None None
MTX 50 11 1 None None None None None
MTX+ TwHF 69 34 24 10 1 2 6 1
69 43 30 7 1 1 10 3
344 122 65 17 2 3 16 4
None
3
2
5
None
8
11
19
3 None None
6 0 7
11 1 10
27 1 17
1
1
0
3
5
None
None
None
2
1
3
None
0
2
2
MA
NU
SC
MTX
Total event s
D
AC
MTX
Lv et al. 2015 [15]
None
None 2
None 2
None 2
None 4
0 5
2 4
2 19
None
None
None
None
14
14
28
None 1 1 None 3
None 1 1 None 2
None None None None None
None None None None None
1 5 5 2 6
1 2 3 1 8
2 9 10 3 19
None
None
None
None
5
3
8
None None None None None None None None
None None None None None None None None
None None None None None None None 2
None None None None None None None 2
1 1 6 1 0 2 2 13
5 3 7 3 1 0 3 16
6 4 13 4 1 2 5 33
CE
Number of patients Patients with AEsa Gastrointestinala Nausea Vomiting Regurgitation Loss of appetite Diarrhoea Abdominal distention Abdominal discomfort ALT elevationa GGT elevation Infection, Upper respiratory tract infection Pneumonia Urinary tract infection Vaginitis Leucocytopeniaa Skin and mucous event Dry skin Rash Baldness Skin pigmentation Ulcer Irregular menstruation Fatigue Weight loss Anemia Palpitations Haematuria Peripheral oedema Headache Other adverse events
MTX+ TwHF 40 15 5 None None None None None
None
PT E
Adverse events (n)
Wang 2013 [25]
PT
[24]
RI
Yang et al. 2013
13
ACCEPTED MANUSCRIPT a
: meta-analysis (fixed model) were did for these adverse events: Patients with AEs: (RR
0.824, 95% CI:0.635–1.068, P = 0.143); Gastrointestinal reaction: (RR 0.834, 95% CI: 0.562–1236, P = 0.365); ALT elevation: (RR 0.632, 95% CI: 0.300–1.333, P = 0.228); Leucocytopenia: (RR 0.809, 95% CI: 0.331–1.975, P = 0.642). 4. Discussion
PT
In recent decades, TwHF plus MTX has become a common strategy for treating RA in
RI
China. Here, we proved the systematic evidence that the MTX plus TwHF may be more
SC
effective than MTX monotherapy for treating active RA. For efficacy, the addition of TwHF increased both the improvement rate (30% response or ACR20) and effective rate (50%
NU
response or ACR50) compared to MTX monotherapy. The addition of TwHF also reduced the
MA
SJC and TJC, shortened the DMS, decreased the level of CRP and rheumatoid factor, and reduced the ERS. TwHF’s effect seems to be dose-dependent, as shown by pooled responder
D
in subgroups of different doses of TwHF (Table 2). Regarding safety, MTX plus TwHF did
PT E
not increase the risk of AEs compared to MTX monotherapy. Thus, taken together, these clinical data indicate that MTX plus TwHF therapy may be a promising therapeutic strategy
CE
for RA.
AC
Two recent meta-analysis studies have also found TwHF extracts, including the tripterygium glycosides, are as effective as, or even more effective than, synthetic DMARDs for treating RA [11, 12]. However, these studies do not focus on combination use of TwHF with other RA drugs, and they the excluded most trials investigating combination therapies. Our study provides additional evidence for use of MTX plus TwHF for treating RA. In addition, two studies, which were excluded because they used MTX at 15 mg/kg in the control group but MTX at 7.5 mg/kg in the MTX plus TwHF groups, found that MTX (7.5 14
ACCEPTED MANUSCRIPT mg/weak) combined with TwHF (30 mg/kg) achieved better or equivalent effect than with MTX (15 mg/d) alone [18, 22]. In addition, Lv et al. recently found that MTX plus TwHF therapy was superior to both MTX and TwHF monotherapies for treating RA [15]. Thus, further large clinical studies are still needed to investigate the long-term efficacy, safety, and
PT
optimized dosages of the combination use of MTX and TwHF for treating RA.
RI
Several limitations in our meta-analysis should be noted: (1) methodologic quality in the
SC
research is poor in some trials, such as unclear random method and that the double blind method is not applied; (2) the included trials were conducted in Chinese population, which
NU
implied a high risk of selection bias; and (3) other interference factors exist, such as
MA
difference in drug dosage.
In addition, to explore some theoretical evidences of MTX plus TwHF therapy for
D
treating RA, we did some preliminary systems biological analyses (detailed information
PT E
please see supplementary information) as in our previous studies [27, 28]. We collected the trusted high confident targets (with comprehensive scores >0.7) of known compounds of
CE
TwHF ingredients from the STITCH database [29], and we compared them to the protein
AC
targets of approved RA drugs (including MTX) from DrugBank (http://www.drugbank.ca) [30] and Pharmainformatics Database (http://bidd.nus.edu.sg/) [31]. As shown in supplementary Fig. 1, we found that TwHF may not inhibited same targets as MTX, but TwHF seems to modulate many targets of other RA drugs, including tumor necrosis factor (TNF , target of etanercept, adalimumab, and infliximab), Prostaglandin G/H synthase 2 (PTGS2, target of etoricoxib), hypoxanthine-guanine phosphoribosyltransferase 1 (HPRT1, target of azathioprine), CD80 (target of belatacept and abatacept), CD86 (target of belatacept 15
ACCEPTED MANUSCRIPT and abatacept), and inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB, target of sulfasalazine). Moreover, by Go-term analysis of all targets of TwHF and MTX , we revealed that TwHF plus MTX may have a combined action on lymphocyte proliferation and its related pathways (as shown in supplementary Fig. 2 and 3). Thus, these systems biological
PT
data additionally support the use of TwHF plus MTX for treating RA, although we may only
RI
collect limited number of targets of TwHF. For example, it has been found triptolide, perhaps
SC
the most effective component of TwHF for treating RA, can block gene transcription by inhibiting transcription factor II Human (TFIIH, a component of transcription machinery)
NU
[32] and may modulate much more genes and proteins than that we collected here [33]. So
MA
the underlying targets and mechanisms concerning anti-rheumatic effect of TwHF are far
D
more complex than our analysis and remain to be further studied.
PT E
Conclusion
The current study preliminarily indicated that MTX plus TwHF may be a more effective
CE
and similarly safe strategy for treating active RA compared with MTX alone. One included
AC
study also suggests MTX plus TwHF may be a more effective strategy for treating active RA compared with TwHF alone [15]. Further large clinical studies are still needed to investigate the long-term efficacy and safety of the addition of TwHF for treating RA.
Conflict of interest None.
16
ACCEPTED MANUSCRIPT Acknowledgments This work was funded by Zhejiang Provincial Natural Science Foundation of China (LY16H280005) and the National Natural Science Foundation of China (81673623), partly supported by “Xin Miao” Student Research Program of Zhejiang Province (2015R410052)
AC
CE
PT E
D
MA
NU
SC
RI
PT
and the Research Program of Zhejiang Chinese Medical University (2015ZG03).
17
ACCEPTED MANUSCRIPT References
AC
CE
PT E
D
MA
NU
SC
RI
PT
[1] D.L. Scott, F. Wolfe, T.W. Huizinga. Rheumatoid arthritis, Lancet. 376 (9746) (2010) 1094-1108. [2] D. Aletaha, T. Neogi, A.J. Silman, J. Funovits, D.T. Felson, C.O. Bingham, 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative, Arthritis Rheum. 62 (9) (2010) 2569-2581. [3] L. Semerano, E. Minichiello, N. Bessis, M.C. Boissier. Novel Immunotherapeutic Avenues for Rheumatoid Arthritis, Trends Mol Med. 22 (3) (2016) 214-229. [4] M.E. Suarez-Almazor, E. Belseck, B. Shea, G. Wells, P. Tugwell. Methotrexate for rheumatoid arthritis, Cochrane Database Syst Rev. (2) (2000) CD000957. [5] E. Zampeli, P.G. Vlachoyiannopoulos, A.G. Tzioufas. Treatment of rheumatoid arthritis: Unraveling the conundrum, J Autoimmun. 65 (2015) 1-18. [6] J.L. Guo, S.X. Yuan, X.C. Wang, S.X. Xu, D.D. Li. Tripterygium wilfordii Hook f in rheumatoid arthritis and ankylosing spondylitis. Preliminary report, Chin Med J (Engl). 94 (7) (1981) 405-412. [7] X.L. Tao, Y. Dong, N.Z. Zhang. A double-blind study of T2 (tablets of polyglycosides of Tripterygium wilfodii hook) in the treatment of rheumatoid arthritis [in Chinese], Zhonghua Nei Ke Za Zhi. 26 (7) (1987) 399-402, 444-395. PMID: 3322706 [8] J. Cibere, Z. Deng, Y. Lin, R. Ou, Y. He, Z. Wang, et al. A randomized double blind, placebo controlled trial of topical Tripterygium wilfordii in rheumatoid arthritis: reanalysis using logistic regression analysis, J Rheumatol. 30 (3) (2003) 465-467. [9] W. Tang, J.P. Zuo. Immunosuppressant discovery from Tripterygium wilfordii Hook f: the novel triptolide analog (5R)-5-hydroxytriptolide (LLDT-8), Acta Pharmacologica Sinica. 33 (9) (2012) 1112-1118. [10] M. Jiang, Q. Zha, C. Zhang, C. Lu, X. Yan, W. Zhu, et al. Predicting and verifying outcome of Tripterygium wilfordii Hook F. based therapy in rheumatoid arthritis: from open to double-blinded randomized trial, Sci Rep. 5 (2016) 9700. [11] H.L. Wang, Q. Jiang, X.H. Feng, H.D. Zhang, L. Ge, C.G. Luo, et al. Tripterygium wilfordii Hook F versus conventional synthetic disease-modifying anti-rheumatic drugs as monotherapy for rheumatoid arthritis: a systematic review and network meta-analysis, BMC Complement Altern Med. 16 (2016) 215. [12] Y. Liu, S. Tu, W. Gao, Y. Wang, P. Liu, Y. Hu, et al. Extracts of Tripterygium wilfordii Hook F in the Treatment of Rheumatoid Arthritis: A Systemic Review and Meta-Analysis of Randomised Controlled Trials, Evid Based Complement Alternat Med. 2013 (2013) 410793. [13] R. Goldbach-Mansky, M. Wilson, R. Fleischmann, N. Olsen, J. Silverfield, P. Kempf, et al. Comparison of Tripterygium wilfordii Hook F versus sulfasalazine in the treatment of rheumatoid arthritis: a randomized trial, Ann Intern Med. 151 (4) (2009) 229-240, w249-251. [14] X. Tao, J. Younger, F.Z. Fan, B. Wang, P.E. Lipsky. Benefit of an extract of Tripterygium Wilfordii Hook F in patients with rheumatoid arthritis: a double-blind, placebo-controlled study, Arthritis Rheum. 46 (7) (2002) 1735-1743. [15] Q.W. Lv, W. Zhang, Q. Shi, W.J. Zheng, X. Li, H. Chen, et al. Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid 18
ACCEPTED MANUSCRIPT
AC
CE
PT E
D
MA
NU
SC
RI
PT
arthritis (TRIFRA): a randomised, controlled clinical trial, Annals Of the Rheumatic Diseases. 74 (6) (2015) 1078-1086. [16] X. Zhang, J. Tan. Clinical investigation of tripterygium glycosides plus methotrexate for treatment of rheumatoid arthritis [in Chinese], Chinese Journal of Medical Guide. (z2) (2012) 602-603. Doi: 10.3969/j.issn.1009-0959.2012.z2.129 [17] W. Zhang, Q. Shi, L.D. Zhao, Y. Li, F.L. Tang, F.C. Zhang, et al. The safety and effectiveness of a chloroform/methanol extract of Tripterygium wilfordii Hook F (T2) plus methotrexate in treating rheumatoid arthritis, J Clin Rheumatol. 16 (8) (2010) 375-378. [18] Y. Wu, Z. Lao, Z. Zhang. Clinical observation on small doses Tripterygium wilfordii polyglycoside combined with methotrexate in treating rheumatoid arthritis [in Chinese], Chinese journal of integrated traditional and Western medicine. 21 (12) (2001) 895-896. Doi: 10.3321/j.issn:1003-5370.2001.12.005 [19] D. Moher, A. Liberati, J. Tetzlaff, D.G. Altman, P. Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, PLoS Med. 6 (7) (2009) e1000097. [20]Z. Xu, H. Zhao, Z. Chen. The efficacy and safety of rufinamide in drug-resistant epilepsy: A meta-analysis of double-blind, randomized, placebo controlled trials, Epilepsy Res. 120 (2016) 104-110. [21] M. Oremus, C. Wolfson, A. Perrault, L. Demers, F. Momoli, Y. Moride. Interrater reliability of the modified Jadad quality scale for systematic reviews of Alzheimer's disease drug trials, Dement Geriatr Cogn Disord. 12 (3) (2001) 232-236. [22] J. Shen, Z. Zhang. Clinical Observation on the Treatment of Rheumatoid Arthritis with Tripterygium Glycosides and Low Dosage Methopterin [in Chinese], Zhejiang journal of integrated traditional chinese and western medicine. 12 (6) (2002) 334-336. Doi: 10.3969/j.issn.1005-4561.2002.06.002 [23] Q. Tan, Q. Xiao. Clinical Evaluation of Tripterygium Wilfordii Polyglycosidium Combined with Methotrexate in Treating Rheumatoid Arthritis and Its Effect on TNF-α and IL-6 [in Chinese], Chinese Journal of Information on Traditional Chinese Medicine. 17 (9) (2010) 7-9. Doi: 10.3969/j.issn.1005-5304.2010.09.004 [24] M. Yang, R. Zhou, B. Li, J. Xu, Y. Shi, H. Mo. Clinical Observation on treatment of rheumatoid arthritis with Tripterygium Wilfordii polyglycoside combined with methotrexate [in Chinese], Chinese Journal of Experimental Traditional Medical Formulae. 19 (17) (2013) 300-304. Doi: 10.11653/syfj2013170300 [25] Y. Wang. Invistagtion of the effcaciou of the cobination of Tripterygium wilfordii with methotrexate treatmet on the rheumatoid arthritis [in Chinese]. Chinese Journal of Primary Medicine and Pharmacy. 20 (11) (2013) 1678-1680. Doi: 10.3760/cma.j.issn.1008-6706.2013.11.038 [26] X. Wang, Z. Luan. Clinical observation on the treatment of rheumatoid arthritis with tripterygium glycosides and methotrexate [in Chinese]. , International Medicine and Health Guidance News. 21 (17) (2015) 2598-2600. Doi: 10.3969/j.issn.1005-4561.2002.06.002 [27] L. Huang, Q. Lv, D. Xie, T. Shi, C. Wen. Deciphering the Potential Pharmaceutical Mechanism of Chinese Traditional Medicine (Gui-Zhi-Shao-Yao-Zhi-Mu) on Rheumatoid Arthritis, Sci Rep. 6 (2016) 22602. [28] L. Huang, Q. Lv, F. Liu, T. Shi, C. Wen. A Systems Biology-Based Investigation into the 19
ACCEPTED MANUSCRIPT
AC
CE
PT E
D
MA
NU
SC
RI
PT
Pharmacological Mechanisms of Sheng-ma-bie-jia-tang Acting on Systemic Lupus Erythematosus by Multi-Level Data Integration, Sci Rep. 5 (2015) 16401. [29] M. Kuhn, C. von Mering, M. Campillos, L.J. Jensen, P. Bork. STITCH: interaction networks of chemicals and proteins, Nucleic Acids Res. 36 (Database issue) (2008) D684-688. [30] V. Law, C. Knox, Y. Djoumbou, T. Jewison, A.C. Guo, Y. Liu, et al. DrugBank 4.0: shedding new light on drug metabolism, Nucleic Acids Res. 42 (Database issue) (2014) D1091-1097. [31] H. Yang, C. Qin, Y.H. Li, L. Tao, J. Zhou, C.Y. Yu, et al. Therapeutic target database update 2016: enriched resource for bench to clinical drug target and targeted pathway information, Nucleic Acids Res. 44 (D1) (2016) D1069-1074. [32] D.V. Titov, B. Gilman, Q.L. He, S. Bhat, W.K. Low, Y. Dang, et al. XPB, a subunit of TFIIH, is a target of the natural product triptolide, Nat Chem Biol. 7 (3) (2011) 182-188. [33] R. Matta, X.X. Wang, H. Ge, W. Ray, L.D. Nelin, Y.S. Liu. Triptolide induces anti-inflammatory cellular responses, American Journal Of Translational Research. 1 (3) (2009) 267-282.
20